Science review: Mechanisms of ventilator-induced injury
© BioMed Central Ltd 2002
Published: 16 October 2002
Acute respiratory distress syndrome (ARDS) and acute lung injury are among the most frequent reasons for intensive care unit admission, accounting for approximately one-third of admissions. Mortality from ARDS has been estimated as high as 70% in some studies. Until recently, however, no targeted therapy had been found to improve patient outcome, including mortality. With the completion of the National Institutes of Health-sponsored Acute Respiratory Distress Syndrome Network low tidal volume study, clinicians now have convincing evidence that ventilation with tidal volumes lower than those conventionally used in this patient population reduces the relative risk of mortality by 21%. These data confirm the long-held suspicion that the role of mechanical ventilation for acute hypoxemic respiratory failure is more than supportive, in that mechanical ventilation can also actively contribute to lung injury. The mechanisms of the protective effects of low tidal volume ventilation in conjunction with positive end expiratory pressure are incompletely understood and are the focus of ongoing studies. The objective of the present article is to review the potential cellular mechanisms of lung injury attributable to mechanical ventilation in patients with ARDS and acute lung injury.
Keywordsacute lung injury acute respiratory distress syndrome alveolar epithelium mechanical ventilation ventilator-induced lung injury
Since the first description of acute respiratory distress syndrome (ARDS) in 1967  and the first description of the treatment of ARDS with mechanical ventilation in 1971 , the only therapeutic invention to convincingly demonstrate a significant reduction in mortality in patients with ARDS and acute lung injury is a lung-protective strategy of mechanical ventilation. No pharmacologic intervention has significantly reduced mortality in a large-scale trial . In the recent National Institutes of Health-sponsored Acute Respiratory Distress Syndrome Network study of 861 patients , ventilation with 6 ml/kg (predicted body weight) and a plateau airway pressure limit of 30 cmH2O reduced mortality from 40 to 31% compared with a conventional tidal volume of 12 ml/kg and similar levels of positive end expiratory pressure (PEEP). These data confirm a long-held suspicion of many clinicians that mechanical ventilation has a double role in ARDS: life saving, but also potentially magnifying the severity of lung injury.
Despite the demonstrated benefits of tidal volume reduction, the mechanisms of the protective effect are incompletely understood. Lung injury related to mechanical ventilation ranges from macroscopic air leaks to intracellular changes in protein phosphorylation signaling cascades and gene expression . The focus of the present article is to review these more subtle changes and their roles in the release of proinflammatory mediators, in changes in permeability, and in changes in ion and solute transport in ventilator-induced lung injury (VILI). Because the precise contribution of mechanical ventilation to lung injury can be difficult to discern in patients with pre-existing acute lung injury, the term ventilator-associated lung injury (VALI) is often used in place of VILI, especially in clinical studies .
Why are patients with ARDS at risk for VALI?
The incidence of ARDS has been estimated at 5–15/100,000 per year [6,7,8,9], but recent data suggest the incidence may be higher . ARDS is a syndrome characterized by the formation of protein-rich pulmonary edema, hyaline membranes, and the influx of neutrophils into the airspace . Nearly all patients with ARDS require mechanical ventilation and are therefore at risk for VALI. This appears to be due in part to the uneven distribution of lung injury and edema in ARDS.
Studies using computerized tomography scanning have demonstrated that the distribution of air and fluid in the lungs of ARDS patients is not uniform . Heterogeneity in the lung results in the functional reduction of the lung volume and predisposes the lung to mechanical forces not encountered in normal physiology. These potentially pathogenetic forces include excessive tensile strain (stretch) from overdistention and interdependence, and shear stress to the epithelial cells of the airspaces due to the movement of air and fluid during tidal ventilation. The latter might be especially important when collapsed lung units are re-expanded.
Effects of mechanical forces on lung injury
In experimental studies, high tidal volume, low PEEP ventilation induces the release of proinflammatory cytokines into the airspaces and bloodstream, neutrophil infiltration into the lung, and the activation of lung macrophages . Tremblay and colleagues  found that isolated, nonperfused rat lungs ventilated with a tidal volume of 40 ml/kg without PEEP for 2 hours had large increases in lavage concentrations of TNF-α, IL-1β, IL-6, and macrophage inflammatory peptide 2. Reduction of the tidal volume to 15 ml/kg or lower reduced the lavage concentrations of these mediators, even if the end inspiratory lung volume was similar. The increase in these cytokines was greater if rats were pretreated with endotoxin, but the differences among the groups persisted. High tidal volume ventilation also increased the expression of c-fos mRNA, a transcription factor important in the early stress response .
The potential importance of proinflammatory mediators in the development of VALI is also supported by data from experimental studies of the effects of anti-TNF-α antibody and IL-1 receptor antagonist on lung injury following surfactant depletion. Imai and colleagues  reported that the pretreatment of surfactant-depleted rabbits with anti-TNF-α antibody prior to the initiation of mechanical ventilation resulted in less severe histologic lung injury and preserved oxygenation. In a similar model, IL-1 receptor antagonist pretreatment reduced endothelial albumin permeability and neutrophil infiltration .
To identify the cellular source of inflammatory cytokines in VILI, Pugin and colleagues  cultured human alveolar macrophages on flexible silastic membranes and exposed the cells to cyclic stretch for up to 32 hours. Cyclic strain induced an increase in the secretion of IL-8. When the macrophages were pretreated with lipopolysaccharide, TNF-α and IL-6 secretion also increased to a greater extent in strained cells compared with static cultures. The authors also noted that there was an increase in nuclear NFκB in macrophages after 30 min of cyclic strain .
In another study by the same group, a variety of cell types, including macrophages, A549 cells, two endothelial cell lines, a bronchial epithelial cell line, and primary lung fibroblasts, were exposed to the same cyclic strain. Of these cell types, only macrophages and A549 cells secreted IL-8 in response to mechanical distention. The relative quantity of IL-8 secreted from macrophages was much greater than the amount secreted from A549 cells. It should be noted that A549 cells are a transformed cell line from a patient with bronchioloavleolar cell carcinoma, and may not respond to cyclic stretch in the same way as primary bronchial or alveolar epithelial cells. In the absence of endotoxin stimulation, cytokines were not secreted in significant amounts from any of the other cell types . The importance of this finding is highlighted by clinical data that demonstrate high levels of IL-8 in pulmonary edema fluid from ventilated patients with ARDS [25,26]. The alveolar macrophage may therefore be an important stretch-responsive cell in the initiation of the inflammatory response observed in VILI. This does not, however, rule out a possible role for other cell types in the propagation of early proinflammatory signaling in VILI.
Held and colleagues  recently reported that mechanical stimuli mediate the release of inflammatory cytokines by increasing phosphorylation of IκB and translocation of NFκB to the nucleus. Interestingly, initiation of NFκB activation in response to mechanical stimuli may be independent of the TRL-4/lipopolysaccharide receptor and can be inhibited by corticosteroids. This finding raises the possibility that pharmacologic therapies could be targeted at ventilator-induced NFκB activation without completely inhibiting the innate immune response .
Clinical studies of protective ventilation
Acute Respiratory Distress Syndrome Network low tidal volume (861 patients) 
VT, 6.2 ± 0.8 ml/kg (PBW); PEEP, 9.4 ± 3.6 cmH2O
VT, 11.8 ± 0.8 ml/kg (PBW); PEEP, 8.6 ± 3.6 cmH2O
Mortality reduced from 40% to 31% with low tidal volume, more ventilator-free days, more organ failure-free days
Amato et al. (53 patients) 
VT, ~6 ml/kg; PEEP, 14.7 ± 3.9 cmH2O (PEEP set by PVC)
VT, ~12 ml/kg; PEEP, 8.7 ± 0.4 cmH2O
Mortality reduced from 71% to 38% with intervention
Stewart et al. (120 patients) 
VT, 7.0 ± 0.7 ml/kg; PEEP, 8.6 ± 3.0 cmH2O
VT, 10.7 ± 1.4 ml/kg; PEEP, 7.2 ± 3.3 cmH2O
Brochard et al. (116 patients) 
VT, 7.1 ± 1.3 ml/kg; PEEP, 10.7 ± 2.9 cmH2O
VT, 10.3 ± 1.7 ml/kg; PEEP, 10.7 ± 2.3 cmH2O
Brower et al. (52 patients) 
VT, 7.3 ± 0.7 ml/kg (PBW); PEEP, 8.3 ± 0.5 cmH2O
VT, 10.2 ± 0.7 ml/kg (PBW); PEEP, 9.5 ± 0.5 cmH2O
Dreyfuss and colleagues  subsequently found that high tidal volume ventilation induced increased permeability edema and that transpulmonary pressure rather than peak airway pressure was the most important determinant of edema formation. Transpulmonary pressure, or the alveolar distending pressure, is analogous to lung volume. These investigators ventilated rats with a peak airway pressure of 45 cmH2O using either positive or negative pressure ventilation, and found similar increases in lung edema and protein permeability. Dreyfuss and colleagues also ventilated rats that had rubber bands applied to the chest and abdomen such that the peak airway pressure was the same but the tidal volume was reduced by roughly one-half, and they found that no edema developed. These findings correlated with scanning electron micrograph studies of lungs exposed to high distending pressures, which reported endothelial and epithelial plasma membrane breaks [29,30].
Parker and Ivey  expanded these findings, showing that changes in intracellular signaling also contributed to the increased permeability edema associated with high tidal volume ventilation. In isolated, perfused lungs, the administration of a β-adrenergic agonist or a phosphodiesterase inhibitor to increase intracellular cAMP resulted in significantly less lung edema and lower protein permeability during high tidal volume ventilation. Furthermore, blocking strain-activated calcium channels with gadolinium also reduced the severity of ventilator-induced pulmonary edema and protein permeability . The same group also reported that inhibition of tyrosine kinase, calcium/calmodulin, or inhibition of phosphorylation of myosin light chain kinase also reduces edema and protein permeability in rats ventilated with large tidal volumes [33,34]. Phosphorylation and activation of myosin light chain kinase results in the formation of cytoskeletal stress fibers and in the formation of intercellular gaps. In vitro studies of endothelial cells have demonstrated that shear stress induces a signaling cascade culminating in myosin light chain kinase activation and the formation of stress fibers .
As with endothelial permeability, alveolar epithelial permeability increases with increasing lung volume. For example, increasing lung volume by the application of PEEP during mechanical ventilation results in increased clearance of inhaled 99mTc-DPTA (molecular weight, 393Da), in excess of what would be predicted from a change in surface area alone [36,37]. Alveolar epithelial permeability to albumin also increases with increasing lung volume [38,39]. In one study, the epithelium of isolated lung lobes distended with fluid to a pressure of 40 cmH2O became more permeable to albumin . This correlated with an increase in the equivalent pore radius from approximately 1 to 5 nm. When entire lungs rather than isolated lobes were tested, the effect was less pronounced because regional differences in transpulmonary pressure were prevented . Which experimental condition most closely approximates clinical VALI is uncertain; however, lung distention near to or exceeding the limits of normal physiology results in increased epithelial permeability even in uninjured lungs.
Ventilation of injured lungs with tidal volumes within a physiologic range can also exacerbate epithelial permeability changes. In a rat model of acid-induced acute lung injury, Frank and colleagues  found that ventilation with 6 ml/kg resulted in less alveolar flooding and less alveolar epithelial injury as measured by plasma levels of a type I cell-specific marker of injury (RTI40) compared with 12 ml/kg and a similar level of PEEP. This finding correlated with histologic and ultrastructural differences in airspace edema and epithelial cell injury. When the tidal volume was further reduced to 3 ml/kg, epithelial injury and airspace edema improved even more. Reducing PEEP during ventilation with a tidal volume of 12 ml/kg, such that the end inspiratory lung volume and mean airway pressures were similar to the 6 ml/kg group, did not prevent epithelial injury or edema . Similar findings have also been reported following surfactant depletion. In this model, tidal volume reduction prevented airspace edema formation and preserved oxygenation, suggesting preserved epithelial barrier function. Interestingly, when surfactant-depleted animals were ventilated with high-frequency oscillatory ventilation (HFOV), edema and histologic injury were further reduced [41,42].
Studies of alveolar epithelial type II cells grown on silastic membranes have helped to characterize the mechanical properties of these cells and have provided insight into the mechanisms of cell injury in VILI. In one study, increasing the duration, amplitude, or frequency of the cyclic strain increased the plasma membrane injury and cell death . Most cell injury occurred within 5 min. If small amplitude deformation was superimposed on basal tonic strain, there was less membrane disruption and cell death compared with a large amplitude stain to same peak level. In this study, the rate of cellular deformation during a single strain did not affect the plasma membrane injury . In another study, plasma membrane disruption induced by cyclic mechanical strain in vitro was dependent on the rate of plasma membrane trafficking to the cell surface. Inhibition of cytoskeletal remodeling had little impact on the cell injury, indicating that mechanical disruption of the cytoskeleton is less important than plasma membrane disruption [44,45]. Although these data do not exclude strain-induced signaling through the cytoskeleton as an important mechanism of VILI, they support the hypothesis that membrane disruption and impaired lipid trafficking may be a major mechanism.
Disruption of the alveolar–capillary barrier is an important mechanism responsible for the formation of alveolar edema, which is characteristic of VILI. This loss of compartmentalization combined with the ventilator-induced amplification of inflammation in acute lung injury may also be an important mechanism of multisystem organ failure, one of the most common causes of death in ARDS (Fig. 1). Several investigators have shown that increased permeability of the alveolar–capillary barrier correlated with the increased levels of proinflammatory mediators in the systemic circulation. von Bethmann and colleagues  reported that, in an isolated perfused murine lung model, ventilation with a transpulmonary pressure of 25 cmH2O compared with 10 cmH2O lead to a significant increase in the concentrations of both TNF-α and IL-6 in the perfusate. In patients with ARDS, concentrations of TNF-α, IL-1β and IL-6 were higher in the arterial blood (obtained via a wedged pulmonary artery catheter) compared with mixed venous blood, suggesting that the lungs were a major source of systemic proinflammatory cytokines in these patients . Several recent studies evaluated the influence of mechanical ventilation strategy on the translocation of bacteria from the lung into the bloodstream [48,49,50]. After intra-tracheal instillation of bacteria, animals ventilated with a higher tidal volume and minimal PEEP (0–3 cmH2O) develop more bacteremia more frequently and more rapidly than animals ventilated with protective strategies.
The release of proinflammatory cytokines into the systemic circulation may have important consequences. In the National Institutes of Health Acute Respiratory Distress Syndrome Network low tidal volume study, as already discussed, plasma levels of IL-6 in the 6 ml/kg tidal volume group were significantly lower than in the conventional tidal volume group. This result was associated with a greater number of organ failure-free days, although this outcome variable may not be independent of mortality. In an experimental study of acid aspiration, Imai and colleagues  reported that 8 hours of mechanical ventilation with an injurious strategy led to epithelial cell apoptosis in the kidney and small intestine, and to increased plasma creatinine levels. An increase in distal ileal permeability has also been reported in rats ventilated with a tidal volume of 20 ml/kg compared with 10 ml/kg . Taken together, these data suggest a role for VALI in the pathogenesis of multisystem organ failure.
Reduced airspace edema clearance
The presence of edema fluid in the airspaces is both an effect of lung injury and a potential mechanism by which VILI is amplified. Edema fluid fills alveoli and promotes airspace collapse by inactivating surfactant and filling airways [53,54,55]. This loss of lung volume leads to heterogeneity of the lung, resulting in even greater overdistention of the remaining lung units . Therefore, if the clearance of edema fluid from the distal airspaces is reduced, a vicious cycle of airspace edema leading to greater lung overdistention and shear stress will ensue (Fig. 1). For example, flooding distal lung units of rats with saline was found to act synergistically with high tidal volume ventilation to increase endothelial permeability to albumin . In this study, the authors also found that permeability to albumin increased as the respiratory system compliance decreased, suggesting that a smaller lung volume was ventilated. As ventilated lung volume decreased, more injury resulted .
The clearance of edema from the airspaces requires the active transport of sodium across the epithelium. Lecuona and colleagues  reported that high tidal volume ventilation induced a reduction in energy-dependent sodium transport. Using alveolar type II cells isolated from rats ventilated with a tidal volume of either 30 or 40 ml/kg, these authors found that sodium-potassium ATPase activity was reduced compared with rats ventilated with a lower tidal volume (10 ml/kg). In another study, airspace edema clearance in lungs isolated from rats ventilated for 40 min with a tidal volume of 40 ml/kg was reduced by approximately 50%. Instilling the airspaces of the isolated lungs with a β-adrenergic agonist restored the rate of airspace edema clearance by increasing the activity and quantity of sodium-potassium ATPase in the basolateral membrane. This effect was blocked by disrupting the microtuble assembly with colchicine, suggesting that it is the translocation of sodium-potassium ATPase from intracellular pools to the plasma membrane that accounts for much of the effect . In an in vivo rat model of acute lung injury, tidal volume reduction from 12 to 3 ml/kg resulted in greater preservation of airspace fluid transport (Fig. 3) . In clinical studies of ARDS patients, preserved airspace fluid clearance correlates with improved survival [60,61]. Taken together, these data suggest that pharmacologic therapy targeted at upregulating airspace fluid clearance may have a role in the prevention of VALI, although further study is necessary.
Prevention of VALI
Prospective clinical studies of patients with ARDS and acute lung injury have demonstrated that protective ventilation strategies incorporating relatively high levels of PEEP and low tidal volumes reduce mortality [4,62,63]. It is clear from the most convincing of these studies  that excessive end inspiratory lung volume is a critical mediator of VALI (Table 1). In this multicenter study, ventilation with similar levels of PEEP but with a tidal volume of 6 ml/kg (predicted body weight) was associated with 31% patient mortality, while ventilation with the conventional 12 ml/kg was associated with 40% mortality. The plateau airway pressure in the low tidal volume group was required to be less than 30 cmH2O (mean, 25 ± 6 cmH2O), compared with a mean plateau airway pressure of 33 ± 8 cmH2O in the conventional tidal volume group. This highlights the fact that the primary difference between the groups was in end inspiratory lung volume.
Furthermore, the mortality benefit persisted regardless of the initial respiratory system compliance. In a smaller study of 53 patients by Amato and colleagues , limiting the tidal volume to less than 6 ml/kg with the PEEP set above the lower inflection point of the static pressure–volume curve (Fig. 2) also reduced mortality, although mortality in the conventional ventilation group in this study was high (71% compared with 38% in the protective ventilation group). Other small studies testing intermediate tidal volumes have not demonstrated a mortality benefit (Table 1) [64,65,66]. These data indicate that limiting the tidal volume to 6 ml/kg in ARDS and acute lung injury patients reduces mortality, but smaller incremental reductions in tidal volume may not. Furthermore, in the Acute Respiratory Distress Syndrome Network study, the mortality benefit appears to be primarily attributable to tidal volume reduction as the PEEP levels were comparable (Table 1).
The other common feature to strategies of protective ventilation is a relatively high level of PEEP. Based on experimental data, the PEEP may minimize VILI by preserving the lung volume, by preserving surfactant function, and by reducing shear forces created by the opening and collapse of airways and alveoli. The best method to select a PEEP level for a given patient with ARDS is not yet known. Although some studies have used the pressure–volume curve of the respiratory system to set the PEEP above the lower inflection point (Fig. 2), others have used arbitrary scales of PEEP. Both strategies, when combined with low tidal volume ventilation, reduce mortality from ARDS [4,62].
In the study of Amato and colleagues , a PEEP level greater than the lower inflection point and a recruitment maneuver at the start of the study were used. In the Acute Respiratory Distress Syndrome Network study, the PEEP was set according to a predetermined scale and not according to the pressure–volume curve. A predetermined scale was used because the relationship between the shape of the pressure–volume curve and events at the alveolar level is affected by numerous factors and is not obvious in every patient [67,68,69,70]. In a subsequent study by the Acute Respiratory Distress Syndrome Network that combined the low tidal volume protocol with a scale incorporating higher PEEP levels compared with the previously tested scale , no additional mortality benefit was observed . Other methods of setting the PEEP, including adjusting the PEEP based on the shape of a constant flow compliance curve, are the subject of ongoing studies .
Based on the recent findings that tidal volume reduction is protective in ARDS, there is renewed interest in HFOV. Combined with a strategy of lung volume maintenance, HFOV would potentially prevent excessive end inspiratory lung volume and would maintain sufficient end expiratory lung volume to a greater degree than conventional ventilation. Preliminary data suggest that this method of ventilation is safe in adults [73,74]. Ongoing studies are comparing HFOV combined with lung volume maintenance to low tidal volume ventilation in children and adults. Previous negative studies of HFOV in children have not always included a protocol for the maintenance of lung volume .
Recognition of patients at risk for VALI
Clinical definition of acute respiratory distress syndrome and acute lung injury 
Acute respiratory distress syndrome
Acute lung injury
Exclusion of alternative diagnosis
Pulmonary artery wedge pressure ≤ 18 mmHg OR absence of clinical evidence for left atrial hypertension
PaO2 : FiO2 ratio ≤ 200
PaO2 : FiO2 ratio ≤ 300
For the first time, clinicians have a well-defined therapeutic intervention that reduces patient mortality from acute lung injury and ARDS. Although the precise mechanisms of the protective effect of low tidal volume ventilation are not fully understood, clinical and experimental data suggest that excessive strain and airspace epithelial shear stress amplify lung inflammation, exacerbate barrier disruption, and promote ongoing pulmonary edema formation. Early recognition of patients with acute lung injury and ARDS (Table 2), and the implementation of protective ventilation is critical if the mortality benefits observed in the recent Acute Respiratory Distress Syndrome Network study are to be realized in clinical practice.
acute respiratory distress syndrome
high-frequency oscillatory ventilation
positive end expiratory pressure
- TNF-α :
tumor necrosis factor alpha
ventilator-associated lung injury
ventilator-induced lung injury.
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